SpyCEP dismantles neutrophil immunity via disorder-driven chemokine remodeling and GAG targeting
Author(s)
Type
Journal Article
Abstract
Streptococcus pyogenes evades neutrophil-mediated immunity by secreting the protease SpyCEP, which inactivates chemokines such as CXCL8; however, the mechanism by which SpyCEP targets CXCL8 for cleavage has remained unclear. This work uncovers an intrinsically disordered autocatalytic maturation loop that binds CXCL8 and induces a conformationally heterogeneous state in the chemokine. A model is proposed in which this disorder-mediated recognition facilitates access to the substrate cleavage site and is compatible with SpyCEP acting at glycosaminoglycan (GAG)-bound CXCL8 reservoirs. This disorder-mediated mode of substrate recognition departs from classical protease–substrate interfaces and identifies the SpyCEP cleaved autocatalytic matu-ration loop (CAML) as a potential target for anti-virulence strategies against S. pyogenes.
Date Issued
2026-07-14
Date Acceptance
2026-05-29
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2026, 123 (28)
ISSN
0027-8424
Publisher
National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
123
Issue
28
Copyright Statement
Copyright © 2026 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
License URL
Identifier
10.1073/pnas.2520164123
Subjects
, and D.G.M. contributed new reagents/analytic tools
R.J.L., S.P.G., A.S., A.D.M., G.T., K.H., D.C., G.H.-Y.W., C.B.H., Y.X., X.F., F.N., Y.L., J.E.P., S.S., and S.M. analyzed data
and R.J.L., S.P.G., A.D.M., G.T., K.H., D.C., G.H.-Y.W., C.B.H., Y.X., X.F., F.N., D.G.M., T.F., Y.L., J.E.P., S.S., and S.M. wrote the paper
Publication Status
Published
Article Number
e2520164123
Date Publish Online
2026-07-09